Stromal cell-derived factor 1 (SDF-1), also known as C—X—C ligand 12, is a small, 8 kDa chemokine involved in leucocyte activation and chemotaxis. The receptors for SDF-1 are C—X—C receptors CXCR7 and CXCR4, the latter of which only binds SDF-1 and ubiquitin. CXCR7 possesses a tenfold higher affinity for SDF-1 than CXCR4. CXCR7 is expressed at very low levels by T cells. SDF-1 promotes cell adhesion, trans-endothelial migration and chemotaxis. SDF-1 can mediate chemorepulsion responses that may have pathophysiological importance.
Several agonists and antagonists that interact with CXCR4 have been developed. The small peptide agonist CTCE-0214 increases migration of CD34+ cells, although at much higher concentrations than SDF-1, and it may be beneficial in treating systemic inflammation. The peptide antagonist CTCE-9908 increases leukocyte uropod formation, but has no effect on migration or adhesion. E. Aboumrad et al. (2007) The CXCR4/CXCL12 (SDF-1) signalling pathway protects non-obese diabetic mouse from autoimmune diabetes. Clinical and experimental immunology 148: 432-439 reported that disruption of SDF-1-CXCR4 binding by the CXCR4 antagonist AMD3100 can accelerate the development of diabetes in adoptive transfer models in mice, and that it can induce beta cell apoptosis; and suggested that CXCR4+ T cells might be protective against diabetes.
ROBO1, a receptor for SLIT2, has been reported to modulate SDF-1-CXCR4 signaling in tumor cells. See A. Prasad et al., Slit protein-mediated inhibition of CXCR4-induced chemotactic and chemoinvasive signaling pathways in breast cancer cells. J Biol. Chem. 2004 Mar. 5; 279(10):9115-24.
C. Sharp et al. (2008) Stromal cell-derived factor-1/CXCL12 stimulates chemorepulsion of NOD/LtJ T cell adhesion to islet microvascular endothelium. Diabetes 57: 102-112 reported that SDF-1 is involved in recruitment of T cells to the pancreas in type 1 diabetes. The injection of mice with antibodies against SDF-1 altered the development of diabetes and suppression of insulitis. Under shear stress in vitro, SDF-1 promoted adhesion and reduced detachment of C57BL/6J T cells, but decreased adhesion and increased detachment of NOD T cells. T cells from C57BL/6J and NOD/ShiLtJ mice had differing affinities for adhering to SDF-1-treated endothelial cells in vitro. The paper speculated that SDF-1 might mediate chemorepulsion of diabetogenic T cell adhesion to islet microvascular endothelium through unknown mechanisms in NOD mice.
Members of the SLIT protein family (SLIT1, SLIT2 and SLIT3) are large glycoproteins that are important for nervous system development. The SLIT proteins are also expressed by epithelial and endothelial cells. The SLIT molecules bind to members of the roundabout, axon guidance receptor (ROBO) family of receptors. They also interact with heparan sulphate chains. In retinal axons in vivo, SDF-1 modulates SLIT and ROBO signalling, while in leucocytes SLIT2 modulates SDF-1-mediated chemotaxis, trans-endothelial migration and adhesion of T cells, and migration of dendritic cells.
MHC haplotypes and autoantibodies have been suggested as markers for autoimmune (type 1) diabetes, but both are subject to high rates of false positives and false negatives.
There is an unfilled need for improved biomarkers for type 1 diabetes. There is also an unfilled need for therapeutic compounds to reduce the progression of type 1 diabetes, and to reduce the risk of developing type 1 diabetes in patients who are at risk of developing type 1 diabetes.